Epilepsy is a syndrome of neurological function disorder resulted from paroxysmal and abnormal discharging of brain neurons, which has disturbances in motion, sensation, consciousness, mental condition and vegetative nervous system. The incidence rate of epilepsy is approximately 1%, which severely threatening life and health of mankind. The neurological electrophysiological basis for epilepsy is excessive and synchronous discharging of neurons, i.e. epileptiform discharging, which mainly results from excitatory disorder of neurons. The neuronal excitability is determined on the balance of activities of potassium ion channels, sodium ion channels and calcium ion channels. If such balance is disturbed, neuronal excitability disorder and further epilepsy seizures are likely to happen.
Potassium ion channels play an important role in adjustment of neuronal excitation, wherein the ionic mechanism is that in concentration of potassium ions in cells is higher than that out of cells, when the depolarization of membrane potential occurs, potassium ion channels are activated, therefore, potassium ions having positive charges outflow off cells, such that membrane potential becomes negative (polarization or hyperpolarization) and neuronal excitability decreases. Recently, genetic research on epilepsy declares that abnormality of potassium ion channels will directly lead to epilepsy (Wulff, H. Et al. Chem Rev 2008, 108 (5), 1744-73.), such as benign familial neonatal convulsions (BFNC).
Besides to protein kinase and G-protein coupled receptor, voltage-gated ion channels (VGICs) is the third kind of signal transduction molecules (Harmar, A. J. et al., Nucleic Acids Res 2009, 37 (Database issue), D680-5.). Among voltage-gated ion channels' 78 of family members, more than a half are potassium ion channels, which are divided into 4 types according to their function and structural features: inward rectifier potassium ion channels (Kir); two pore potassium ion channels (K2p); Ca2+-activated potassium ion channels (KCa) and voltage-gated potassium ion channels (KV) (Wulff, H. et al., Nat Rev Medicament Discov 2009, 8 (12), 982-1001.).
Voltage-gated potassium ion channels (KV) is an important member of potassium ion channels superfamily, which has 12 members (KV1.X-KV12.X). Wherein, KCNQ channels is the 7th member of the voltage-gated potassium ion channels (Kv7), which includes five subtypes, namely, KCNQ1 to KCNQ5. Compared with other potassium ion channels, the activation threshold of KCNQ channels is low, in other words, KCNQ channels can be opened at a voltage lower than action potential threshold (−60 mV), KCNQ channels has an slow activation process and will not inactivated on persistent depolarization. Those characters endow KCNQ channels with a basal level in adjustment of cellular excitability. The opening of KCNQ channels may decrease the cellular excitability, while inhibiting them will evoke membrane potential depolarization of neurocytes, such that the excitability is increased and more neural impulses are evoked.
Based on the said advantageous of KCNQ-targeted sites, the agonist thereof is deemed to be an effective medicament for treating epilepsy. By activating potassium ion channels to decrease neuronal excitability, such agonists of potassium ion channels not only can be used in treatment of epilepsy but also can be used in treatment of other diseases induced by exorbitant neuronal excitability, such as convulsion, neuropathic pain, acute ischemic stroke or neurodegenerative diseases.
Reported KCNQ agonists are mainly as follows.
1) A compound of following structure is disclosed in U.S. Pat. No. 5,384,330, which characterized in that it has a benzene ring substituted by two amino groups at positions next to each other.

2) Agonists of KCNQ channels having following structure are described in Patent No. WO2005/087754 A1, which characterized in that it has a benzene ring substituted by two amino groups at positions opposite to each other, wherein, the nitrogen atom in one of the amino group is in a saturated ring (or a heterocycle when W is O), while the two hydrogen atoms at the positions next to another nitrogen atom on the benzene ring are substituted by R1 or R2.

3) Patent No. WO2008024398-B1 records compound of following structure, which has a similar structure to that of compounds in Patent No. WO2005/087754, except for an additional ring fused to the saturated ring.

At present, the most representative KCNQ agonist is commercially available retigabine having following structure, which is an anti-epilepsy medicament developed by GSK (GlaxoSmithKline):

Retigabine is the first KCNQ agonist, which has been investigated in a systematic procedure. By activating KCNQ2-5, retigabine is mainly used for treatment of adults suffered from partial seizures of epilepsy. Retigabine can be absorbed in short time, its maximum concentration in plasma will be reached 1.5 h to 2 h after administration of single dosage.
Retigabine has an electron-rich benzene ring substituted by three nitrogen atoms, wherein two nitrogen atoms are at positions next to each other, and one nitrogen atom is present in the form of amino. Such structural feature causes retigabine to be oxidized and deteriorated in synthesis and storage. In addition, the inventors of the present invention have found that the concentration of retigabine in mice's brain tissue is not high in research on tissue distribution of the medicament, which may influence the maximum effectiveness thereof. Thereby, it is necessary to develop an agonist of potassium ion channels, which has higher activity and more stable property, especially contributes to increase the concentration distribution in brain tissue, so as to be used in developing of medicaments for treating neuropathic diseases, such as epilepsy, convulsion, neuropathic pain, acute ischemic stroke or neurodegenerative diseases.
The inventors of the present application also find that when the nitrogen atom in —NH-(secondary amine) of retigabine is further substituted, the resulting compound not only retains or increase the retigabine's activity of opening potassium ion channels, but also has a higher distribution concentration in brain tissue than that of retigabine. Consequently, the compound of the present invention exhibits a better treatment effect.